Programmed death-1 immune checkpoint blockade (PD-1 ICB) is now FDA-approved for the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Some patients can have dramatic beneficial responses to this type of treatment, but the majority of patients do not respond. We aim to enhance the number of patients that responses to these treatments. One approach is to combine different immunotherapies with each other or with other types of anti-cancer treatment like chemotherapy, radiation, or targeted therapies. One of the major barriers to effective immunotherapy seems to be the presence of immunosuppressive immune cells alongside the anti-tumor immune cells within the tumor. In head and neck cancers, immature myeloid cells and regulatory T-cells are potent suppressors of anti-tumor immunity. Our laboratory has investigated how to use targeted drugs that block the ability of immunosuppressive myeloid cells into the tumor to allow the anti-tumor immune cells to work more effectively after they have been activated by immunotherapy. Based on new investigation from our laboratory, drugs that block the recruitment of myeloid cells into tumors are being investigated in first-in-human clinical trials at the NIH clinical center. A different approach to allowing PD-1 ICB immunotherapy to work better is to alter the timing of treatment. Recent work from our laboratory has demonstrated that giving PD-1 ICB before surgery allows the immune system to see the tumor cells better than if the treatment is given after surgery. When the immune system detects and reacts against tumor cells better, it can better prevent the tumor from coming back. This work has contributed to the development of two new innovative clinical trials at the NIH Clinical Center that involve the administration of immunotherapy before surgical excision of both HPV-negative and HPV-positive tumors. Another line of thinking suggests that T cells, the immune cell type most studied for their ability to detect and kill cancer cells, may not work in some patients with cancer because of underlying mutations in the tumor cells that make them undetectable. In this case, another type of immune cell called NK cells may still be able to detect and kill the tumor cells. Working closely with other investigators in the National Cancer Institute, our laboratory has studied newly developed immunotherapies based on NK cells that be effective in treating cancers that cannot be effectively treated by immunotherapies designed to activate T cells. This laboratory work is ongoing with anticipated first-in-human clinical trials at the NIH Clinical Center using these NK cellular therapies. Our laboratory also studies a rare disorder called recurrent respiratory papillomatosis. Patients with RRP, caused by HPV, develop papilloma tumors in their throat, voicebox, windpipe and lings that can lead to severe voice disturbance or airway obstruction. Traditional treatment involves repeated surgery that leads to high recurrent rates. We are studying how to treat these tumors with immunotherapy, and have performed the first clinical trial that has established the safety and clinical activity of PD-1 ICB in patients with RRP. In collaboration a colleague in the National cancer Institute, we have received a Cancer Moonshot Award to further discover and develop new immunotherapies that someday could be used to treat not only RRP but other virally-driven pre-cancerous disorders. We are excited to continue our work investigating new immunotherapies, with the ultimate goal of moving each promising treatment into early phase clinical trials at the NIH and other academic medical centers.